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Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations

Title
Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations
Authors
Chung K.W.Kim S.B.Park K.D.Choi K.G.Lee J.H.Eun H.W.Suh J.S.Hwang J.H.Kim W.K.Seo B.C.Kim S.H.Son I.H.Kim S.M.Sunwoo I.N.Choi B.O.
Ewha Authors
김원기서정수최경규박기덕이정희최병옥은효원
SCOPUS Author ID
서정수scopusscopus; 최경규scopus; 박기덕scopus
Issue Date
2006
Journal Title
Brain
ISSN
0006-8950JCR Link
Citation
vol. 129, no. 8, pp. 2103 - 2118
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Mutations in the mitofusin 2 (MFN2) gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot-Marie-Tooth 2A (CMT2A) and hereditary motor and sensory neuropathy VI (HMSN VI). It is well known that HMSN VI is an axonal CMT neuropathy with optic atrophy. However, the differences between CMT2A and HMSN VI with MFN2 mutations remained to be clarified. Therefore, we studied the phenotypic characteristics of CMT patients with MFN2 mutations. Mutations in MFN2 were screened in 62 unrelated axonal CMT neuropathy families. We calculated CMT neuropathy scores (CMTNSs) and functional disability scales (FDSs) to quantify disease severity. Twenty-one patients with the MFN2 mutations were studied by brain MRI. Ten pathogenic mutations were identified in 26 patients from 15 families (24.2%). Six of these mutations had not been reported, and de novo mutations were observed in five families (33.3%). The electrophysiological patterns of affected individuals with the MFN2 mutations were typical of axonal CMT; however, the clinical and electrophysiological characteristics were markedly different in early (<10 years) and late disease-onset (≥10 years) groups. All patients with an early onset had severe CMTNS (≥21) and FDS (6 or 7), whereas most patients with late onset had mild CMTNS (≤10) and FDS (≤3). We identified two HMSN VI families with the R364W mutation in the early onset group; however, two other families with the same mutation did not have optic atrophy. In addition, two early onset families with R94W mutations, previously reported for HMSN VI, did not have visual impairment. Interestingly, eight patients had periventricular and subcortical hyperintense lesions by brain MRI. In the late-onset group, three patients had sensorineural hearing loss and two had bilateral extensor plantar responses. We found that MFN2 mutations are the major cause of axonal CMT neuropathy, and that they are associated with variable CNS involvements. Phenotypes were significantly different in the early and late disease-onset groups. Our findings suggest that HMSN VI might be a variant of the early onset severe CMT2A phenotype. © The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
DOI
10.1093/brain/awl174
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자연과학대학 > 화학·나노과학전공 > Journal papers
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